17alpha-halogenoethinylestranes



United States Patent 3,347,880 170z-HALOGENOETYLESTRANES Cecil H. Robinson, Cedar Grove, N..ll., assignor to Schering Corporation, Bloomfield, Ni, a corporation of New Jersey N0 Drawing. Filed Oct. 5, 1962, Ser. No. 228,748 19 Claims. (Cl. 260-3975) This invention relates to a new class of steroids, to processes for their preparation and to novel intermediates produced thereby. More particularly, this invention relates to therapeutically valuable steroids of the estrane series having a l7u-halogenoethinyl group. Specifically, this invention relates to 17a-halogenoethinylestradiol, 16, 16-difluoro-17a-halogenoethinylestradiol, and to derivatives thereof and to methods for their preparation.

Included among the novel steroids of this invention are 17a-halogenoethinylestranes of the following general formula:

wherein R is a member of the group consisting of H, lower alkyl, and an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms; X is a halogen having an atomic weight greater than 19' and less than 100; Y is a member of the group consisting of and and Z is a member of the group consisting of H and an acid radical of a hydrocarbon carboxylic acid having up to 8 carbon atoms.

By lower alkyl is contemplated hydrocarbon radicals having up to 8 carbon atoms, thus including radicals such as methyl, ethyl, propyl, ter-butyl, hexyl, octyl, and the like.

The acid radicals at C-3 and C-17 of the compounds of this invention are preferably from lower alkanoic acids such as acetic, propionic, butyric, valeric, caproic, enanthic, and the like. Also included are acid radicals of aryl carboxylic acids such as benzoic and of dibasic acids such as succinic.

Thus, included in this invention are compounds such as 17u-ch1oroethinylestradiol (l7a-chloroethinyl 1,3,5 ()-estratrine-3,17fi-diol), 16,16-difluoro 17m chloroethinylestradiol (16,lfi-difluoro-17a-chlor0ethinyl 1,3,5 (l0)-estratrine-3,l7,8 diol), 17a bromoethinylestradiol, 16,16-difiuoro-17a-bromoethinylestradiol, the 3-methyl ether derivatives thereof, the 3-methoxy-17-acetate derivatives thereof, the 3-acetate, and 3,17-diacetate esters thereof.

The preferred compounds of this invention are those possessing a 17a-chloroethinyl group and, in particular,

17a-chloroethinylestradiol.

The novel steroids of this invention are conveniently prepared from estrone (1,3,5(10)-estratriene-3-ol-17- one), 16,16-difluoroestrone (16,16-difluoro-l,3,5(10)-estratriene-3,8-ol), and their 3-lower alkoxy derivatives, by halogenoethynation of the 17-keto function utilizing techniques similar to those known in the art. Thus, for example, treatment of estrone with lithium chloroacetylide (prepared by the action of methyl lithium on 1,2-dichloroethylene) yields a compound of this invention, 170L-Cl1l01'0- ethinylestradiol. In like manner, estrone methyl ether is converted to 17a-chloroethinylestradiol methyl ether.

In similar manner, the action of bromoethinyl lithium on estrone yields 17u-bromoethinylestradiol of this invention.

The starting compounds possessing a 16,16-difluoro moiety, i.e. 16,16-difiuoroestrone and the lower alkoxy ethers thereof, are prepared by techniques such as described in U.S. Patent No. 3,048,605. By this process, the action of perchlorylfiuoride on 3 methoxy-l6-hydroxymethylene-1,3,5(l0)-estratriene-17-one yields the starting compound 16,16-difluoroestrone 3-methyl ether which may be cleaved with hydroiodic acid/ acetic acid to the alcohol, 16,16-difiuoroestrone. Conversion of the thus prepared l6,l6-difiuoroestrone and 16,16-difluoroestr0ne 3- methyl ether to compounds such as 15,16-difillOIO-l7ozbromoethinylestradiol, 16,16 difluoro-17wbromoethinylestradiol 3-methyl ether, 16,16-difluoro-17a-chloroethinylestradiol and 16,1o-difluoro-17a-chloroethinylestradiol 3- methyl ether is then effected via the process of this invention as described hereinabove.

The 3-alkyloxy-17a-halogenoethinyl-1,3,5 (10)-estratrienes of the general formula possessing an ester group at C-17 are conveniently prepared by known techniques from the corresponding 3-alkoxy-17I3-hydroxy-17a-hal0- genoethinylestratrienes by esterification with pyridine and an acid anhydride. For example, 17u-chloroethinyl-1,3,5 (10)-estratriene-3,17/3-diol 3-methyl ether when heated with acetic anhydride in pyridine yields the 17-acetate, i.e. 17a chloroethinyll,3,5(10)-estratriene-3,l7B-diol 3- methyl ether 17-acetate. By substituting other lower alkanoic acid anhydrides such as propionic anhydride or caproic anhydride; or a dicarboxylic acid anhydride such as succinic or phthalic anhydride; or acid halides of aryl carboxylic acids such as benzoyl chloride, the corresponding 17-ester is obtained, i.e. the 17-propionate, l7- caproate, l7-succinate, 17-phthalate and 17-benzoate respectively of l7a-chloroethinyl-l,3,5 (10)-estratriene-3, 17fi-diol B-methyl ether.

When preparing 3,17-diesters of the general formula, the corresponding 3,17-diol is preferably reacted in pyridine with at least two moles of an acid anhydride or two moles of an acid chloride per mole of steroid. Usually an excess of acid anhydride or acid halide is used, and it is often desirable to apply heat to hasten the esterification process. For example, 16,16-diiluoro-17a -chloroethinylestradiol dibenzoate is obtained from the 16,16-difiuoro- 17a-chloroethinylestradiol by reaction with a 2-molar excess of benzoyl chloride.

The 3 acyloxy-17a-halogenoethinyl-17fi-hydroxyestratrienes of the general formula are conveniently prepared from the corresponding 3,l7-dihydroxy-l7a-halogenoethinyl estratrienes by selective esterification at C-3 with pyridine and a lower alkanoyl anhydride, or with pyridine and an acid chloride of an aryl carboxylic acid such as benzoyl chloride. For example, 17a-chloroethinyl-1,3, 5(10)-estratriene-3,17,B-diol reacted with approximately a molar equivalent of acetic anhydride in pyridine yields the 3-monoacetate, i.e. 17a-chloroethinyl-1,3,5(10)-estratriene-3,17,B-diol 3-acetate. Similarly, reaction with approximately a molar equivalent of benzoylchloride in pyridine yields the 3-mon0benzoate, i.e. 17ot-chloroethinyl-1,3, 5 10)-estratriene-3,17,8-diol 3-benzoate.

By varying reaction conditions and utilizing a combination of known techniques there are obtained compounds of the general formula having dissimilar ester groups at C-3 and C17. For example, reaction of a 3-acyloxy- 16,16-difiuoro-17a-hydroxyestratriene with an acid anhydride or acid halide having an acid radical other than that at the 3-position, such as the reaction of 17oc-Chl0f06lhinyl-1,3,5(10)-estratriene-3,17B-diol 3-benzoate with ace- 3 tie anhydride in pyridine at elevated temperatures will yield the mixed 3,17-diester, l7a-chloroethinyl-1,3,5(l0)- estratriene-3,17fl-diol 3-benzoate 17-acetate.

A compound of my invention possessing a hydroxy group at C-3 and an ester group at C-17, such as 16,16- difluoro-l7ot-chloroethinylestradiol l7-acetate and 17achloroethinylestradiol 17-acetate are conveniently prepared by known techniques from the corresponding diesters, 16,16-difluoro-17a-chloroethinylestradiol diacetate and 17zx-chloroethinyl estradiol diacetate by partial hydrolysis such as with potassium hydroxide or 1% potassium carbonate in methanol respectively.

The compounds of this invention, and particularly 170cchloroethinylestradiol, possess estrogenic activity and thus are useful in the treatment of ailments such as menopausal disorders, hypogenitalism and sexual infantilism, amenorrhea and oligomenorrhea associated with hypogonadism, postpartum breast engorgement and pruritus or kraurosis vulvae. My compounds are preferably administered orally, a convenient dosage form being tablets containing 0.02 mgm., 0.05 mgm. or 0.5 mgm. of a l7a-chloroethinylestradiol of this invention in admixture with a pharmaceutically acceptable excipient. The dosage of compound used on a patient will vary depending on the nature and severity of the patients symptoms.

The following examples are for illustrative purposes only and are not to be construed as limiting, the limit of my invention being defined by the appended claims.

EXAMPLE 1 1 7a-chlor0ethinyl-1,3,5(10 -estratriene-3,I7,8-di0l (1 7m-chl0r0ethinylestradiol) To 560 mg. of lithium metal in anhydrous ether (50 ml.) is added dropwise, over 30 minutes, a solution of methyl iodide (2.5 ml.) in ether ml.). The mixture is then left for one hour at room temperature, and is then cooled to 0 C. A solution of 1,2-dichloroethylene (3.1 ml.) in either ml.) is then added dropwise, over 15 minutes, and the mixture is stirred at room temperature for minutes. A solution of estrone (1.15 g.) in tetrahydrofuran (20 ml.) is then added dropwise over 15 minutes, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is then cooled to C. and solid ammonium chloride (5 g.) is added, followed by Water. The ether is evaporated, the resulting aqueous suspension is filtered, and the residue on the filter is washed with water, dried, and chromatographed on Florisil. Elution with hexane-ether (9:1) gives a solid which is crystallized from acetone-hexane to give 17a-chloroethinyl-l,3,5(10)-estratriene-3,l7B-diol. M.P. 19019l C., [u] -l6 (dioxan).

EXAMPLE 2 17a-chl0r0ethz'nyl-1,3,5(10)-estratriene-3,17fl-diol 3-methyl ether (17a-chl0roethinylestradiol 3-methyl ether) A solution of estrone B-methyl ether (1.15 g.) in tetrahydrofuran (20 ml.) is allowed to react with lithium chloroacetylide exactly in the manner of Example 1, and the crude product is chromatographed on Florisil. Elu tion with hexaneether (9: 1) gives a solid which is crystallized from acetonehexane to give 17a-chloroethinyl-1,3,5 (10)-estratriene-3,l7,6-diol 3-methyl ether. M.P. 168' C., [u] -13 (dioxan).

EXAMPLE 3 1 6,1 6 difluoro-I 7a-chl0r0ethinyl-1 ,3,5(10 -estratriene-3,

1 7/3-diol 3-methyl ether (16,16-diflu0r0J7a-chl0roethinylestradiol 3-methyl ether) 16,l6-difiuoro-1,3,5(10)-estratriene-3-ol-l7-one is allowed to react with lithium chloroacetylide (prepared by the action of methyl lithium on 1,2-dichloroethylene) in a manner similar to that described in Example 1. The resultant product is isolated in the described manner to 4 give 16,16 difiuoro-lM-chloroethinyl 1,3,5 (10)-estratriene 3,17/3-dio1 3-methyl ether.

In a similar manner, 16,16-difluoro-1,3,5 (l0)-estratriene-3-ol-17-one 3-ethyl ether is allowed to react with lithium chloroacetylide to give 16,16-difluoro-17a-chloroethinyl-l,3,5(10)-estratriene-3,17 3-diol 3-ethyl ether.

EXAMPLE 4 16,16-diflu0r0-1 7ot-chl0r0ethinyl-1,3,5 (10 -estratriene-3, 17,8-di0l (16,16-diflu0r0-1 7oa-chloroethinylestradiol In a manner similar to that described in Example 1, 16,16-difluoro-1,3,5 10) -estratriene-3-ol-17-one is allowed to react with lithium chloroacetylide. The resultant product is isolated in the described manner to give 16,16-difluoro 17cc chloroethiuyl 1,3,5(10) estratriene 3, 17fl-di0l.

EXAMPLE 5 17u-br0m0ethinylestrwdiol, the 3-methyl ether thereof, and the 16,16-diflu0r0 derivatives thereof A solution of estrone (l,3,5(10)-estratriene-3-ol-l7- one) is treated in the exact manner as described in Example 1 except that instead of 1,2-dichloroethylene (3.1 ml.) there is used 1,2-dibromoethylene (5.94 ml.). The resultant product is isolated in the described manner to give bromoethinyl-1,3,S(10)-estratriene-3,17/3-di0l (17ot-bromoethinylestradiol In a similar manner, estrone 3-methyl ether, 16,16- difluoro estrone, 16,16-difluoro estrone 3-methyl ether, and 16,16-difiuoro estrone 3-ethyl ether are each allowed to react with lithium bromoacetylide (prepared by the action of methyl lithium on 1,2-dibromoethylene) and there is obtained, respectively, 17a-bromoethinylestradiol 3- methyl ether, 16,16-difiuoro-17ot-bromoethinylestradiol, 16,l6-difluoro-17u-bromoethinylestradiol 3-methy1 ether, and 16,16-difluoro 1704 bromoethinylestradiol 3-ethyl ether.

EXAMPLE 6 3-alk0xy-1 7ot-haZ0gen0ethinyl-17fl-aciyl0xy-L3fi (10)- estratrienes A. 17-LOWER ALKANOATE ESTERS To 1 g. of 3-methoxy-17a-chloroethinyl-1,3,5(10)- estratriene-17fi-ol (the compound of Example 2) in 10 ml. of pyridine is added 10 ml. of acetic anhydride. The solution is refluxed under an atmosphere of nitrogen until esterification is substantially complete as determined by paper chromatography using dinitrophenylhydrazine as the indicating reagent. The reaction mixture is cooled, poured into water, and extracted with ether. The ether extracts are combined, washed with 5% aqueous sodium bicarbonate solution, then water, dried over sodium sulfate, filtered, then distilled in vacuo to give a residue substantially of 3-methoxy-17a-chloroethinyl-1,3,5(10)-estratriene-l7fi-ol l7-acetate.

In a similar manner, 3-methoxy-16,16-difluoro-17otchloroethinyl 1,3,5(l0) estratriene 17B ol, S-ethoxyl6,16-difluoro-17a-chlor0ethinyl 1,3,5 (10) estratriene- -01, 3-methoxy 170a bromoethinyl-1,3,5(10)-estratriene-17B-ol, and 3-methoxy 16,16 diflllOIO-17oc-bTOII10- ethinyl-1,3,5(l0)-estratriene-l7fl-ol are each reacted with acetic anhydride in pyridine in the above-described manner to give, respectively, 3-methoxy-16,16-difluoro-17uchloroethinyl 1,3,5 (10) estratriene-17,8-ol 17-acetate, 3-ethoxy-16,16-difiuoro 17a chloroethinyl-l,3,5(l0)- estratriene 17,8 o1 17-acetate, 3-methoxy 17a bromothinyl-1,3,5 (10)-estratriene 1713 o1 17-acetate, and 3- methoxy 16,16 difiuoro-l7ot-bromoethinyl-1,3,5(10)- estratriene-17/8-ol l7-acetate.

Similarly, by substituting other lower alkanoic acid anhydrides such as propionic, valeric, or caproic for acetic anhydride in the above procedure, there is obtained the corresponding 17-propionate, 17-valerate and 17-caproate, respectively, of 3-methoxy-16,l6-difiuoro 170a chloroethinyl 1,3,5 (10) estratriene-17fl-ol, 3-ethoxy-16,16-difiuoro-17u-chloroethinyl 1,3,5(10) estratriene-17501, S-methoxy 17cc bromoethinyl 1,3,5 (10) estratriene- 175-01, and 3-methoxy-16,16-difluoro 17a bromoethinyl- 1,3,5 10) -estratriene-17,B-ol.

B. 17HEMISUCCI*NATE ESTERS AND SODIUM *SAL'DS THEREOF To 1 g. of 3-meth0xy-17a-chloroethinyl-1,3,5(10)-estratriene-17fl-ol in 10 ml. of pyridine is added 1 g. of succinic anhydride. The mixture is heated on a steam bath for one hour, then cooled and diluted with water. A solid separates which is filtered, washed with water, and then dried to give S-methoxy 17oz chloroethinyl-1,3,5(10)- estratriene-17501 17-hemisuccinate.

To 1 g. of 3-methoxy-17u-chloroethinyl-1,3,5(10)-estratriene-175ml 17-hemisuccinate suspended in 10 ml. of water is added 1.0 ml. of a 10% aqueous solution of sodium hydroxide. The resultant aqueous solution is evaporated in vacuo to a residue of substantially 3-methoxy- 17a-chloroethinyl 1,3,5(10) estratriene 17p 01 17- sodium hemisuccinate.

Similarly, in the procedure described hereinabove, by substituting for 3-methoxy-17u-chloroethinyl-1,3,5 (10)- estratriene-17B-ol the 3-alkoxy estratrienes prepared in Examples 3 and 5, there is obtained, respectively, the 17- hemisuccinate and 17-sodium hemisuccinate of 3-methoxy- 16,16-difluoro-17a-chloroethinyl 1,3,5 (10) estratriene- 175-01, 3-ethoxy 16,16 difiuoro-l7a-chloroethinyl-1,3,5 (10)-estratriene-l7B-ol, 3-methoxy 17a brornoethinyl- 1,3,5(10)-estratriene-17fi-ol, 3-methoxy 16,16 difluoro- 17a-bromoethinyl 1,3,5 (10) estratriene-17,301 and 3- ethoxy 16,16 difiuoro 17a bromoethinyl-1,3,5(10)- estratriene-175ml.

c. 3-METHOXY-l'M-CHLOROETHINYL-l,3,5(10)-ESTRA- TRIENE-HBOL l7-BENZOATE 1 g. of 3-methoxy-17a-chloroethinyl-l,3,5(10)-estratriene-l7/8-0l in 10 ml. of pyridine and 2 ml. of benzoyl chloride is reacted in a manner similar to that described in Example 6A to give 3-methoxy-17a-chloroethinyl-1,3,5 (10)-estratriene-17fi-ol 17-benzoate.

In a similar manner, by substituting the alkoxy estratrienes prepared in Examples 3 and 5 for 3-methoxy-17ozch1oroethinyl-1,3,5(10)-estratriene-17fi-ol in the above procedure, there is obtained the corresponding 17-benzoate ester.

EXAMPLE 7 Preparation of S-acyloxy esters A. PREPARATION OF 3-ALKA NOYL ESTERS A solution of 1g. of 17a-chloroethinyl-1,3,5(10)-estratriene-3,17Bdiolin m1. of pyridine and 2 ml. of acetic anhydride is left overnight at room temperature. Water is added and the aqueous mixture extracted with ether. The ether extracts are combined, washed with 2 N hydrochloric acid, then water, dried over sodium sulfate, filtered, and evaporated in vacuo to give a residue substantially of 17a-chloroethinyl 1,3,5(10) estratriene-3,17 3- diol 3-acetate.

In a similar manner, 16,16-difluoro-17u-chloroethinyl- 1,3,5 10) estratriene 3,176 diol, 17oz bromoethinyl- 1,3,5(10)-estratriene-3,17,B-diol, and 16,16-difill0IO-17ccbromoethinyl-1,3,5 (10)-estratriene-3,17;8-diol are each reacted with acetic anhydride in pyridine to give, respectively, 16,1G-difluoro-17a-chloroethiny1 1,3,5 (10) estratriene-3,17;8-diol 3-acetate, 17a-bromoethinyl-1,3,5 l0)- estratriene 3,175 diol 3-acetate and 16,16-difiuoro-17abromoethinyl-1,3,5( 10) -estrat1iene-3,17 3-diol 3-acetate.

By substituting other acid anhydrides such as propionic, valeric, t-butylacetic anhydride for acetic anhydride in the above procedure, there are obtained the corresponding propionate, valerate, and t-butyl acetate of the aforenamed compounds.

B. PREPARATION OF 3-BENZOATE ESTERS To 1 g. of 17a-chloroethinyl-1,3,5(10)-estratriene- 3,17fi-diol in 10 ml. of pyridine is added 3 ml. of benzoyl chloride. The solution is left at room temperature for twenty-four hours; water is added and the aqueous mixture extracted with ether. The ether extracts are combined, washed with 2 N hydrochloric acid, then water, dried over sodium sulfate, filtered and distilled in vacuo to give a residue substantially of 17u-chloroethinyl-1,3,5(10)-estratriene-3,l7,B-di0l 3-benzoate.

In a similar manner, 16,16-difluoro-17u-chloroethinyl- 1,3,5 (10) estratriene 3,175 diol, 17a bromoethinyl- 1,3,5 10)-estratriene-3,l7fi-diol, and 16, l6-difluoro-17abromoethinyl-1,3,5(10)-estratriene-3,l7fi-diol are each reacted with benzoyl chloride in pyridine to give, respectively, 16,16-difluoro-17a-chloroethinyl-1,3,5 10)-estratriene 3,17,8-diol 3-benzoate, 17a-bromoethinyl-l,3,5(10)- estratriene-3,17f3-diol 3-benzoate and 16,16-(llfl11010-17ubromoethinyl-1,3,5 10) -estratriene-3, 17,8-diol 3-benzoate.

EXAMPLE 8 Preparation of 3,17-ai-l0wer alkanoyl and 3,1 7-dibenz0ate esters 17a-bromoethinyl-1,3,5 10)-estratriene-3,17B-diol diacetate,

17a-bromoethinyl-1,3,5 10) -estratriene-3,17/3diol dibenzoate,

16, 16-difiuoro- 17a-chloroethinyl- 1,3,5 10) -estratriene- 3,17B-diol diacetate,

16,16-difluoro-17a-chloroethinyl-1,3,5( 10) -estratriene- 3,17fi-diol dibenzoate,

16,16-difluoro-l7a-brom0ethinyl-1,3,5 (10) -estratriene- 3,17/3-diol diacetate, and

16,16-dlfi11010-17oc-bI0ITl06thjI1y1-1,3,5( 10)-estratriene- 3,17;8-dio1 dibenzoate.

I claim: 1. A compound selected from the group consisting of a 17a-halogenoethinylestradiol of the following general formula:

wherein R is a member selected from the group consisting of H, lower alkyl, and an acid residue of a hydrocarbon carboxylic acid having up to 8 carbon atoms; Z is a mem ber selected from the group consisting of H and an acid residue of a hydrocarbon carboxylic acid having up to 8 carbon atoms; X is a halogen having an atomic weight greater than 19 and less than and Y is a member selected from the group consisting of and H F 7 17u-ch1oroethinylestradiol. 16, 16-difluoro-17u-chloroethinylestradiol. 17a-bromoethinylestradiol. 16,16-difluoro-17e-brornoethinylestradiol. l7u-chloroethiny1estradiol 3-methy1 ether. 17a-bromoethinylestradiol 3-methyl ether. 16,16 difluoro-17a-chloroethinylestradiol 3-methyl ether.

9. 16,16 difiuoro 17a-bromoethiny1estradiol 3-methyl ether.

10. 3 OR-l7a-cl1loroethinyl-1,3,5(10)estratriene-17}8- 01 wherein R is an acid residue of a carboxylic acid having up to 8 carbon atoms.

11. 17a-chloroethinylestradiol 3-acetate.

12. 17a-chloroethinylestradi-ol 3-benzoate.

13. 17a-chloroethinylestradiol diacetate.

14. 17a-chloroethinylestradio1 3-methyl ether 17-acetate.

15. 17a-chloroethinylestradio1 3-methy1 ether 17-hemisuccinate.

16. In the process of preparing a compound selected from the group consisting of steroids of the following general formula:

wherein R is a member selected from the group consisting of H, lower alkyl, and an acid residue of a hydrocarbon carboxylic acid having up to 8 carbon atoms; Z is a member selected from the group consisting of H and an acid residue of a hydrocarbon carboxylic acid having up to 8 carbon atoms; X is a halogen having an atomic weight greater than 19 and less than 100; Y is a member selected from the group consisting of the step which comprises reacting a member selected from the group consisting of a compound of the following general formula:

actant selected from the group consisting of lithium chloroacetylide and lithium bromoacetylide.

17. The process which comprises reacting estrone with lithium v chloro acetylide.

18. A compound of the following formula 19. A compound of the following formula:

wherein R is a member selected from the group consisting of hydrogen and methyl.

40 References Cited UNITED STATES PATENTS 3,057,885 10/1962 Goldkamp 260397.4 3,062,845 11/1962 Mills et al. 260397.4 45 OTHER REFERENCES Fried et al., Journal Amer. Chem. Soc. vol. 83 (1961), pp. 4663-4664 relied on.

Robinson et al., Journal Amer. Chem. Soc., vol. 82 50 (1960), pp. 5256-5257 relied on.

ELBERT L. ROBERTS, Primary Examiner.

LEWIS GOTTS, Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A 17A-HALOGENOETHINYLESRADIOL OF THE FOLLOWING GENERAL FORMULA: 